Evaluation of the efficacy and tolerability of levetiracetam as add-on therapy in intractable epilepsy of children

Objective One-third of epilepsy of children is refractory, and this study was conducted to evaluate the efficacy and adverse events of levetiracetam as add-on therapy in the treatment of refractory epilepsy of children. Materials & Methods In this quasi-experimental study, seizures frequency and side effects of 314 children aged 1-14 years with refractory epilepsy were referred to the Pediatric Neurology Clinic of Shahid Sadoughi Medical Sciences University, Yazd, Iran, and treated with levetiracetam for six months, were evaluated. Results: We evaluated 142 girls and 172 boys with a mean age of 6.78±2.12 years. At the end of six months of treatment with levetiracetam, 20% became seizure-free, 28% had more than 50% decrease in seizure frequency, 38% did not have a notable change in seizure frequency, and 14% experienced an increase in seizure frequency. Good response (stopping of all seizures or more than 50% reduction in seizure frequency) was seen in 51% of mixed types, 61% of myoclonic seizures, 64% of generalized tonic-clonic seizures, 69 % of partial seizures, 100 % of tonic seizures, and in 40 % of atonic seizures. Levetiracetam was significantly more effective in partial seizures, idiopathic epilepsies, and children with normal developmental status and normal brain MRI. Twelve children discontinued the treatment due to severe drowsiness, restlessness, and exacerbation of seizures. Transient and mild side effects, including somnolence, anorexia, fatigue, headache, ataxia, and diplopia, were seen in 9% (N=28) of patients. Conclusion: Levetiracetam could be considered an efficient and safe adjunct therapy in treating refractory epilepsy in children.


Introduction
Epilepsy as a brain disorder is defined based on " the International League Against Epilepsy (ILAE), by any of the following conditions: 1. At least two unprovoked (or reflex) seizures occurring >24 h apart 2. One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next ten years 3. Diagnosis of an epilepsy syndrome" (1).
"The clinical diagnosis of epilepsy usually requires the occurrence of at least one unprovoked epileptic seizure with either a second such seizure or enough electroencephalogram (EEG) and clinical information to demonstrate an enduring predisposition to develop recurrences convincingly.
For epidemiologic and, commonly, for clinical purposes, epilepsy is considered when two or more unprovoked seizures occur in a time frame of longer than 24 hr. The cumulative lifetime incidence of epilepsy is 3%, and the annual prevalence is 0.5-1.0%. " (2) Intractable or refractory epilepsy is defined by the ILAE as recurrence of at least one seizure in a week despite taking two or three appropriate antiepileptic drugs (AEDs) with sufficient dosage (3), which includes approximately one-third of newly treated patients with epilepsy. (4) Intractable seizures, on the one hand, may lead to more extensive brain insult and, on the other hand, result in frequent referring to neurologists, hospitalization, financial burden, and the negative impact on the quality of life of the affected child and his or her family. Complete elimination of seizures or effective control of seizures is necessary to reduce epilepsy-related morbidity and mortality, and new AEDs with greater efficacy and fewer side effects are fiercely needed. Levetiracetam (LEV) is one of the newest antiepileptic drugs that has entered the market since 2000 and has been approved by the Food and Drug Administration since 2006 and is currently available in pills of 250, 500, and 1000 mg and also syrup (100 mg/ ml) in our country.
For metabolism, it does not enter the cytochrome P450 enzyme system and is excreted directly and unchanged from the kidney, and its dose adjustment in patients with kidney failure is inevitable. In children, well toleration of the drug, its linear pharmacokinetics and complete oral absorption, the low extent of metabolism, and no interaction with other AEDs, lead to low discontinuation rates.
The most common reported side effects in children Iran J Child Neurol. Spring 2022 Vol. 16 No. 2 are behavioral symptoms (irritability, agitation, hyperactivity, and cognitive slowing), and CNS adverse events, such as somnolence, asthenia, and dizziness, are usually less than other AEDs. LEV side effects are reversible, mild, and transient. Its mechanism of action is not precisely understood and has multiple mechanisms, but possibly act through voltage-dependent sodium channels that lead to a suppressive effect on the presynaptic release of excitatory neurotransmitter (glutamate and aspartate) release, as well as an increase in the concentration of inhibiting neurotransmitter gamma-aminobutyric acid in the brain, reducing the flow with no apparent impact on the activity of NMDA glutamate receptors, and carbonic anhydrase of the erythrocyte. The effective dose in pediatric patients is 20-40 mg/kg/day, given in two or three divided doses; however, it may be given up to 60 mg/kg/day. There is no direct correlation between LEV blood levels and seizure control, the drug side effects, or administered dosage. Therefore, the measurement of blood levels of LEV does not seem to be helpful. (2,5,6) Its efficacy has substantially controlled generalized tonic-clonic, myoclonic, and partial seizures in children. (5)(6)(7)(8)(9)(10)(11)(12)(13)(14) Given that children with refractory epilepsy represent a significant percentage of referral cases to pediatric neurology clinics and because LEV has lately been introduced in our country, this study was conducted with the primary objective of evaluation of the efficacy, safety, and tolerability of this medication as add-on therapy in the treatment of intractable pediatric epilepsy.

Materials & methods
In this quasi-experimental study, all consecutive Stopping of all seizures or reduction of more than 50% in the weekly frequency of seizure was considered as a good response to LEV, and also the following classification was considered on this basis: • Seizure-free: No more seizure attack was experienced.
• Improved: The patient's seizure frequency was reduced by more than 50%.
• Unchanged: No notable change was seen in seizure frequency.

Results
Three hundred thirty eligible children were enrolled in the study, but 16 patients were excluded from the study due to not returning or inadequate compliance and finally, 314 children, including 142 girls and 172 boys with a mean age of 6.78 ± 2.12 years, were evaluated and completed the entire course of the study. The age of onset of seizures was two months to 12.5 years, with a mean age of 2.01± 0.82 years. MRI was normal in 119 (38%), and 243 patients (77.3%) had developmental delay.
In this study, 106 children (33.7%) showed a mixed type of seizures (more than one type of seizure), and the major seizure type was myoclonic in 89 children (28.3%), generalized tonic-clonic in 59 The frequency distribution of good response to LEV based on some patients' characteristics is shown in Table 1, which indicates that LEV was significantly more effective in partial seizures, idiopathic epilepsies, children with normal developmental status, and normal brain MRI. Also, no statistically significant differences were seen from viewpoints of sex distribution, family history of epilepsy, and mean age of patients in both groups.
In the responders group, the mean age of onset of seizures was higher than in non-responders. In the present research, the mean dose of LEV for seizure control was 27.9 ± 5.4 mg/kg/day.
A possible explanation for these discrepancies is the difference in sample size, age of patients, duration of the study, drug pharmacokinetics, race, and geographic location.
In the present study, a good response to LEV was more frequent in epileptic children with normal brain MRI. In Japan, 72% (13 of 18 children) of children with a good response (more than 50% reduction in seizures frequency) had normal brain MRI. (6) In this research, a good response was seen in 51%  (16), irritability (5,10), and hyperactivity and impulsivity (10) were reported in other studies.
However, age has been shown to have a significant contribution in experiencing adverse reactions, and the difference in adverse effects observed in these studies can be related to differences in the evaluated age groups by these studies.
In the present study, the aforementioned adverse effects in the majority of children were transient and mild and did not require the drug discontinuation, and LEV add-on therapy was safe and tolerable in the treatment of refractory epilepsy of children that is consistent with the results of other studies. (5,9,10, 12 , 16-19) In conclusion, based on the results of this study,